Methods and devices for modulation of heart valve function

ABSTRACT

Methods and devices for modulating heart valve function are provided. In the subject methods, a heart valve is first in structurally modified. Blood flow through the structurally modified heart valve is then monitored, and the heart is paced in response to the monitored blood flow. Also provided are devices, systems and kits that find use in practicing the subject methods. The subject methods find use in a variety of applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 U.S.C. §119 (e), this application claims priority to thefiling date of the U.S. Provisional Patent Application Ser. No.60/567,320 filed Apr. 30, 2004; the disclosure of which is hereinincorporated by reference.

INTRODUCTION Background of the Invention

Congestive heart failure (CHF), which is often associated with anenlargement of the heart, is a leading cause of death. As a result, themarket for the treatment of CHF is becoming increasingly prevalent. Forinstance, the treatment of CHF is a leading expenditure of Medicare andMedicaid dollars in the United States of America. Typically, thetreatment of CHF enables many who suffer from CHF to enjoy an improvedquality of life.

Referring initially to FIG. 1, the anatomy of a heart, specifically theleft side of a heart, will be described. The left side of a heart 104includes a left atrium 108 and a left ventricle 112. An aorta 114receives blood from left ventricle 112 through an aortic valve 120,which serves to prevent regurgitation of blood back into left ventricle112. A mitral valve 116 is disposed between left atrium 108 and leftventricle 112, and effectively controls the flow of blood between leftatrium 108 and left ventricle 112.

Mitral valve 116, which will be described below in more detail withrespect to FIG. 2 a, includes an anterior leaflet and a posteriorleaflet that are coupled to cordae tendonae 124 which serve as “tensionmembers” that prevent the leaflets of mitral valve 116 from openingindiscriminately. When left ventricle 112 contracts, cordae tendonae 124allow the anterior leaflet to open upwards until limited in motion bycordae tendonae 124. Normally, the upward limit of opening correspondsto a meeting of the anterior and posterior leaflets and the preventionof backflow. Cordae tendonae 124 arise from a columnae camae 128 or,more specifically, a musculi papillares of colummae camae 128.

Left ventricle 112 includes trabeculae 132 which are fibrous cords ofconnective tissue that are attached to wall 134 of left ventricle 112.Trabeculae 132 are also attached to an interventricular septum 136 whichseparates left ventricle 112 from a right ventricle (not shown) of heart104. Trabeculae 132 are generally located in left ventricle 112 belowcolumnae camae 128.

FIG. 2 a is a cut-away top-view representation of mitral valve 116 andaortic valve 120. Aortic valve 120 has a valve wall 204 that issurrounded by a skeleton 208 a of fibrous material. Skeleton 208 a maygenerally be considered to be a fibrous structure that effectively formsa ring around aortic valve 120. A fibrous ring 208 b, which issubstantially the same type of structure as skeleton 208 a, extendsaround mitral valve 116. Mitral valve 116 includes an anterior leaflet212 and a posterior leaflet 216, as discussed above. Anterior leaflet212 and posterior leaflet 216 are generally thin, flexible membranes.When mitral valve 116 is closed (as shown in FIG. 2 a), anterior leaflet212 and posterior leaflet 216 are generally aligned and contact oneanother to create a seal. Alternatively, when mitral valve 116 isopened, blood may flow through an opening created between anteriorleaflet 212 and posterior leaflet 216.

Many problems relating to mitral valve 116 may occur and theseinsufficiencies may cause many types of ailments. Such problems include,but are not limited to, mitral regurgitation. Mitral regurgitation, orleakage, is the backflow of blood from left ventricle 112 into the leftatrium 108 due to an imperfect closure of mitral valve 116. That is,leakage often occurs when a gap is created between anterior leaflet 212and posterior leaflet 216.

In general, a relatively significant gap may exist between anteriorleaflet 212 and posterior leaflet 216 (as shown in FIG. 2 b) for avariety of different reasons. For example, a gap may exist due tocongenital malformations, because of ischemic disease, or because aheart has been damaged by a previous heart attack. A gap may also becreated when congestive heart failure, e.g., cardiomyopathy, or someother type of distress causes a heart to be enlarged. When a heart isenlarged, the walls of the heart, e.g., wall 134 of a left ventricle,may stretch or dilate, causing posterior leaflet 216 to stretch. Itshould be appreciated that anterior leaflet 212 generally does notstretch. As shown in FIG. 2 b, a gap 220 between anterior leaflet 212and stretched posterior leaflet 216′ is created when wall 134′stretches. Hence, due to the existence of gap 220, mitral valve 116 isunable to close properly, and may begin to leak.

Leakage through mitral valve 116 generally causes a heart to operateless efficiently, as the heart must work harder to maintain a properamount of blood flow therethrough. Leakage through mitral valve 116, orgeneral mitral insufficiency, is often considered to be a precursor toCHF. There are generally different levels of symptoms associated withheart failure. Such levels are classified by the New York HeartAssociation (NYHA) functional classification system. The levels rangefrom a Class 1 level which is associated with an asymptomatic patientwho has substantially no physical limitations to a Class 4 level whichis associated with a patient who is unable to carry out any physicalactivity without discomfort, and has symptoms of cardiac insufficiencyeven at rest. In general, correcting for mitral valve leakage may besuccessful in allowing the NYHA classification grade of a patient to bereduced. For instance, a patient with a Class 4 classification may havehis classification reduced to Class 3 and, hence, be relativelycomfortable at rest.

A variety of treatments used to correct for mitral valve leakage or,more generally, CHF, have been developed. In certain instances, theimplantation of replacement valves is employed to treat mitral valverelated conditions. Valves from animals, e.g., pigs, may be used toreplace a mitral valve 116 in a human. While the use of a pig valve mayrelatively successfully replace a mitral valve, such valves generallywear out, thereby requiring additional open surgery at a later date.Mechanical valves, which are less likely to wear out, may also be usedto replace a leaking mitral valve. However, when a mechanical valve isimplanted, there is an increased risk of thromboembolism, and a patientis generally required to undergo extended anti-coagulant therapies.

One repair technique which has been shown to be effective in treatingincompetence, particularly of the mitral and tricuspid valves, isannuloplasty, in which the effective size of the valve annulus iscontracted by attaching a prosthetic annuloplasty ring to theendocardial surface of the heart around the valve annulus. Theannuloplasty ring comprises an inner substrate of a metal such asstainless steel or titanium, or a flexible material such as siliconerubber or Dacron cordage, covered with a biocompatible fabric or clothto allow the ring to be sutured to the heart tissue. The annuloplastyring may be stiff or flexible, may be split or continuous, and may havea variety of shapes, including circular, D-shaped, C-shaped, orkidney-shaped. Examples are seen in U.S. Pat. Nos. 4,917,698, 5,061,277,5,290,300, 5,350,420, 5,104,407, 5,064,431, 5,201,880, and 5,041,130,which are incorporated herein by reference.

During an annuloplasty procedure, an annuloplasty ring may be implantedon the mitral valve to cause the size of a stretched mitral valve 116 tobe reduced to a relatively normal size. FIG. 3 is a schematicrepresentation of a representative annuloplasty ring. An annuloplastyring 304 is shaped approximately like the contour of a normal mitralvalve. That is, annuloplasty ring 304 is shaped substantially like theletter “D.” Typically, annuloplasty ring 304 may be formed from a rod ortube of biocompatible material, e.g., plastic, that has a DACRON meshcovering.

In order for annuloplasty ring 304 to be implanted, a surgeon surgicallyattaches annuloplasty ring 304 to the mitral valve on the atrial side ofthe mitral valve. Conventional methods for installing ring 304 requireopen-heart surgery which involve opening a patient's sternum and placingthe patient on a heart bypass machine. As shown in FIG. 4, annuloplastyring 304 is sewn to a posterior leaflet 318 and an anterior leaflet 320of a top portion of mitral valve 316. In sewing annuloplasty ring 304onto mitral valve 316, a surgeon generally alternately acquires arelatively large amount of tissue from mitral tissue, e.g. a one-eighthinch bite of tissue, using a needle and thread, followed by a smallerbite from annuloplasty ring 304. Once a thread has loosely coupledannuloplasty ring 304 to mitral valve tissue, annuloplasty ring 304 isslid onto mitral valve 316 such that tissue that was previouslystretched out, e.g., due to an enlarged heart, is effectively pulled inusing tension applied by annuloplasty ring 304 and the thread whichbinds annuloplasty ring 304 to the mitral valve tissue. As a result, agap, such as gap 220 of FIG. 2 b, between anterior leaflet 320 andposterior leaflet 318 may be substantially closed off. After the mitralvalve is shaped by ring 304, the anterior and posterior leaflets 320,318 will reform to create a new contact line and will enable mitralvalve 318 to appear and to function as a normal mitral valve.

Once implanted, tissue generally grows over annuloplasty ring 304, and aline of contact between annuloplasty ring 304 and mitral valve 316 willessentially enable mitral valve 316 to appear and function as a normalmitral valve. Although a patient who receives annuloplasty ring 304 maybe subjected to anti-coagulant therapies, the therapies are notextensive, as a patient is only subjected to the therapies for a matterof weeks, e.g., until tissue grows over annuloplasty ring 304.

In a modification of the above described annuloplasty approach,percutaneous annuloplasty devices and procedures have been developed, inwhich an annuloplasty device is positioned in the coronary sinus.

Annuloplasty rings may also be utilized in combination with other repairtechniques such as resection, in which a portion of a valve leaflet isexcised, the remaining portions of the leaflet are sewn back together,and a prosthetic annuloplasty ring is then attached to the valve annulusto maintain the contracted size of the valve. Other valve repairtechniques in current use include commissurotomy (cutting the valvecommissures to separate fused valve leaflets), shortening mitral ortricuspid valve chordae tendonae, reattachment of severed mitral ortricuspid valve chordae tendonae or papillary muscle tissue, anddecalcification of the valve leaflets or annulus. Annuloplasty rings maybe used in conjunction with any repair procedures where contracting orstabilizing the valve annulus might be desirable.

A second type surgical procedure which is generally effective inreducing mitral valve leakage involves placing a single edge-to-edgesuture in the mitral valve. With reference to FIG. 5 a, such a surgicalprocedure, e.g., an Alfieri stitch procedure or a bow-tie repairprocedure, will be described. An edge-to-edge stitch 404 is used tostitch together an area at approximately the center of a gap 408 definedbetween an anterior leaflet 420 and a posterior leaflet 418 of a mitralvalve 416. Once stitch 404 is in place, stitch 404 is pulled in to forma suture which holds anterior leaflet 420 against posterior leaflet 418,as shown. By reducing the size of gap 408, the amount of leakage throughmitral valve 416 may be substantially reduced.

Another surgical procedure which reduces mitral valve leakage involvesplacing sutures along a mitral valve annulus around the posteriorleaflet. A surgical procedure which places sutures along a mitral valvewith be described with respect to FIG. 5 b. Sutures 504 are formed alongan annulus 540 of a mitral valve 516 around a posterior leaflet 518 ofmitral valve 516, and may be formed as a double track, e.g., in two“rows,” from a single strand of suture material. Sutures 504 are tiedoff at approximately a central point 506 of posterior leaflet 518.Pledgets 546 are often positioned under selected sutures 504, e.g., atcentral point 506, to prevent sutures 504 from tearing through annulus540. When sutures 504 are tied off, annulus 540 may effectively betightened to a desired size such that the size of a gap 508 betweenposterior leaflet 518 and an anterior leaflet 520 may be reduced.

Although efficient in restoring valve function, the above procedures andtechnologies do not address the decline in pump function of the heartmuscle. In addition, the above described procedures are typicallyavailable only to patients with severely damaged valves.

There is, therefore, a continued need to develop new approaches torepairing cardiac, and particularly mitral valve, function, where ofparticular interest would be the development of a system for improvingmitral valve function while at the same time restoring pump function ofthe heart. The present invention addresses this need.

RELEVANT LITERATURE

U.S. Pat. Nos. 5,243,976; 5,316,001; 5,376,112; 5,489,297; 5,554,177;5,593,424; 5,709,695; 5,792,194; 5,824,066; 6,292,693; 6,539,261;6,626,838; 6,643,546; 6,537,314; 6,565,603; 6,709,456; 6,718,985; and6,723,038.

SUMMARY OF THE INVENTION

Methods and devices for modulating heart valve function are provided. Inthe subject methods, a heart valve is first in structurally modified.Blood flow through the structurally modified heart valve is thenmonitored, and the heart is paced in response to the monitored bloodflow. Also provided are devices, systems and kits that find use inpracticing the subject methods. The subject methods find use in avariety of applications.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a cross-sectional front-view representation of the left sideof a human heart.

FIG. 2 a is a cut-away top-view representation of the mitral valve andthe aortic valve of FIG. 1.

FIG. 2 b is a cut-away representation of a stretched mitral valve and anaortic valve.

FIG. 3 is a representation of an annular ring that is suitable for usein performing a conventional annuloplasty procedure.

FIG. 4 is a representation of a mitral valve and an aortic valve afterthe annular ring of FIG. 3 has been implanted.

FIG. 5 a is a representation of a mitral valve and an aortic valve aftera single edge-to-edge suture has been applied to reduce mitralregurgitation.

FIG. 5 b is a representation of a mitral valve and an aortic valve aftersutures along a mitral valve annulus have been applied to reduce mitralregurgitation.

FIG. 6 provides a representative view of a system according to thesubject invention as positioned to treat mitral valve regurgitation, asdescribed in greater detail in the Experimental Section, below.

FIG. 7 provides a diagram of the operational relationship of the variouscomponents of the system as controlled by the central processing unit.

DETAILED DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Methods and devices for modulating heart valve function are provided. Inthe subject methods, a heart valve is first in structurally modified.Blood flow through the structurally modified heart valve is thenmonitored, and the heart is paced in response to the monitored bloodflow. Also provided are devices, systems and kits that find use inpracticing the subject methods. The subject methods find use in avariety of applications.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits; ranges excluding either orboth of those included limits are also included in the invention.

Methods recited herein may be carried out in any order of the recitedevents which is logically possible, as well as the recited order ofevents.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Furthermore, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

As summarized above, the present invention provides methods and devices,as well as systems and kits, for modulating, and specifically improving,valve function in a subject. In further describing the subjectinvention, the subject methods are reviewed first in greater detail,followed by a more in-depth description of representative embodiments ofsystems and devices for practicing the subject methods, as well as areview of various representative applications in which the subjectinvention finds use. Finally, a review of representative kits accordingto the subject invention is provided.

Methods

As summarized above, the present invention provides methods ofmodulating the function of a target valve in a subject. The target valveis generally a cardiac valve (by which is meant that the valve ispresent in a heart), such as an aortic valve, mitral valve, tricuspidvalve, etc. In many representative embodiments, the target valve is amitral valve.

The subject in which the target valve is present in many embodiments ofthe present invention is a mammalian subject, i.e., is a “mammal” or“mammalian,” where these terms are used broadly to describe organismswhich are within the class mammalia, including the orders carnivore(e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats),lagomorpha (e.g. rabbits) and primates (e.g., humans, chimpanzees, andmonkeys). In many embodiments, the hosts will be humans.

As indicated above, the subject methods are methods of modulatingfunction of the target valve. By modulating is meant altering orchanging the function of the target valve. In many representativeembodiments, the modulating results in an improvement in the function ofthe target valve, e.g., in the form of reduced or even eliminatedregurgitation. Where the modulation results in reduced regurgitation,the magnitude of the reduction may be at least about 5-fold, such as atleast about 10-fold, including at least about 20-fold, as compared to asuitable control.

In practicing the subject methods, the target valve is firststructurally altered. By structurally altered is meant that the targetvalve is surgically changed or modified in a manner that results in achange in the physical structure of the valve, e.g., in terms ofdiameter of the valve annulus, the physical orientation of two or moreof the leaflets relative to each other, the physical structure of theleaflets and/or adjacent cardiac tissue, etc.

The target valve may be structurally altered using any convenient anddesirable valve modification protocol, where a variety of suitableprotocols and devices for practicing the same have been developed andmay be employed. Representative valve alteration protocols of interestinclude, but are not limited to: annuloplasty procedures, in which thediameter of the target valve annulus is effectively reduced; proceduresin which one or more sutures are placed on the valve leaflets in orderto modify leaflet and therefore valve function; procedures in whichtissue modifications, e.g., plications or folds, are produced proximalto the target valve to alter its function; and the like.

In many representative embodiments of the present invention, thestructural modification or alteration of the target valve is achieved byan annuloplasty procedure. Any convenient annuloplasty procedure may beemployed, where such procedures are reviewed generally in the Backgroundsection, above. The annuloplasty device and protocol may be open heart,e.g., where the device is positioned interstitially, or percutaneous, asis known in the art. Representative annuloplasty devices and protocolsfor their use are further described in U.S. Pat. Nos. 6,709,456;6,565,603; 6,537,314; 5,824,066; 5,709,695; 5,593,424; the disclosuresof which are herein incorporated by reference.

Following structural modification of the target valve, as describedabove, flow through the structurally modified target valve is monitored,where the obtained or observed flow data in this step is then employedas input in determining the desired pacing of the heart, as described ingreater detail below. In this monitoring step of the subject methods,measurement of blood flow can be obtained through various blood flowmeasurement techniques. Representative blood flow measurement techniquesof interest include, but are not limited to: sonic Doppler flowmeasurement techniques, e.g., continuous wave (CW) Doppler flowmeasurement and pulsed Doppler flow measurement; optical laser Dopplerflow measurement; transit time flow measurement; thermal dilution flowmeasurement; and electromagnetic flow measurement.

As is known in the art, Doppler ultrasound imaging systems detect aDoppler shift in the frequency of a transmitted signal reflected fromultrasound reflectors, and display returns only from such reflectors.The magnitude of the Doppler shift corresponds to the velocity of theultrasound reflectors, and the polarity of the Doppler shift correspondsto the direction of movement. Conventional Doppler images are thus ableto provide an indication of both blood flow velocity and blood flowdirection, thereby allowing arterial blood flow to be differentiatedfrom venous blood flow.

Blood flow through the target valve may also be monitored by usingelectromagnetic flow techniques to estimate blood flow velocity. In oneembodiment of this technique, at least first and second (i.e., two ormore) electrodes are disposed across the target valve such that theblood flow is in a direction that is substantially orthogonal to avector between the first and second electrodes. A permanent magnet orelectromagnet is used to create a magnetic field through the bloodvessel in a direction that is substantially orthogonal to both thedirection of blood flow and the vector between the first and secondelectrodes. As a result, ionized particles within the blood flow aredeflected toward one of the first and second electrodes, resulting in avoltage difference therebetween that is proportional to the blood flowvelocity. In certain of these embodiments, a pulsed current may beemployed to generate the magnetic field, as desired, e.g., to reduce theamount of heat generated by the electromagnet. In these representativeembodiments, the duty cycle may range from about 0-100%, such as fromabout 0.01 to about 10%, including from about 1 to about 5%.

In yet other embodiments, blood flow through the target valve may bemonitored using thermal dilution techniques to estimate blood flow. Inone embodiment of this technique, a heater is used to pulsedly heat theblood, and the heated blood pulse is detected by a temperature sensorlocated at a known distance from the point of heating in the directionof the blood flow, where the temperature sensor may be at the valve orat a distance away from the valve, e.g., in the aorta. Volumetric bloodflow is calculated from the time between the heating of the blood pulseand the detection of the blood pulse. Several heated blood pulses aretypically introduced and detected to produce a more accurate blood flowestimate. In certain embodiments, a single thermistor may be used forboth heating and detection. A heated thermistor is introduced into theblood vessel such that it is in thermal contact with the blood flow, andcooling of the thermistor is effected by the blood flow. Blood flow at ahigher velocity cools the thermistor at a higher rate than blood flow ata lower velocity. The energy delivered to the thermistor to maintain thethermistor at a constant temperature is proportional to blood flowvelocity. Alternatively, the thermistor can be heated to a knowntemperature, and the time required to cool the thermistor to a second,lower temperature will be inversely proportional to blood flow. Incertain embodiments, the thermally sensed flow magnitude may be coupledwith a direction component, which may be derived from the particularstage of the cardiac cycle at which the measurement is taken. Asdesired, suitable algorithms may be employed to achieve this coupling ofmagnitude of flow and direction.

In yet other embodiments, laser Doppler techniques may be employed toestimate blood flow. The blood flow is illuminated with a coherentmonochromatic light source signal. A resulting backscatteredDoppler-shifted light signal is received at an optical detector, anddemodulated such as by mixing with the monochromatic light sourcesignal. Blood flow velocity is estimated from a resulting basebandedDoppler-shifted frequency of the received light signal.

In certain representative embodiments, as described further below, theblood flow measuring device that is employed to monitor blood flowthrough the structurally altered target valve is part of an implantabledevice that was used in the target valve structural modification. Inother words, the blood flow monitoring device is part of an implantablevalvular structural modification device, such as an annuloplasty ring.In certain representative embodiments, the blood flow monitoring deviceis integrated with the implantable valve structure modification device.

In representative embodiments where the structural modification deviceis an implantable annuloplasty ring, such as an interstitialannuloplasty ring, the integrated flow monitoring element is anelectromagnetic flow monitoring element. In these embodiments, amagnetic field is established by the device and detected variations inthe established magnetic field are employed to determine flow velocityat a given time, as well as over or during a given temporal period. Themagnetic field may be established using a number of differentapproaches, such as through of electromagnets; use of two or morepermanent magnets, including rare earth magnets, such as neodymium; useof a material, such as a ferromagnetic material, within the magneticfield inducing components, to increase the magnitude of the magneticfield; and the like. In certain embodiments, the established magneticfield may be modulated by a carrier frequency, such that the voltagemeasured by the electrodes would also be modulated by a carrierfrequency, such as 500 Hz, thus making it possible to create aflow-dependent voltage signal at a frequency range outside of the rangeof frequencies generated by pacemakers and/or the myocardium. In certainembodiments, a voltage sensing unit associated with the two or moreelectrodes.

In representative embodiments of annuloplasty devices having integratedelectromagnetic flow sensor elements, the implantable annuloplastydevice may have a partial ring shape within the plane of the valve and awire may be looped around the device in a manner sufficient to producethe desired magnetic field across the plane of the valve. In certainembodiments, the apparatus may be one that positions two or more magnetsarranged around the circumference of the diameter of the valve, e.g.,such as 2 or more, 3 or more, 4 or more, 5 or more, 10 or more, 20 ormore, etc. In embodiments having a sufficient number of differentmagnets, the direction of the magnetic can be changed within the planeof the vale activating a current producing field into the vale, and alsoactivating a subset of magnets pointing out of the vale.

As summarized above, in practicing the subject methods, data obtained bymonitoring the flow through the valve, e.g., by using a separate flowmeter or a flow meter integrated with an implantable valve structuremodulation (such as annuplasty) device, is used to at least partiallymodulate electrical stimulation (also referred to herein as pacing) ofthe heart. In other words, obtained flow meter data or information isemployed to influence, e.g., determine or set, etc., how the heart ispaced, e.g., from an implanted cardiac stimulation or pacing device.

In such embodiments, the implanted cardiac pacing device is one that isimplanted in a manner sufficient to modulate function of thestructurally altered target valve. Any convenient pacing device andprotocol may be employed, where protocols and implantable devices foruse therein for modulating valve function via electrical stimulation orpacing are known in the art. The pacing device employed may having asingle pacing site or multiple pacing sites. Representative suchprotocols and devices include those described in U.S. Pat. Nos.6,643,546; 6,292,693; 5,554,177; the disclosures of which are hereinincorporated by reference. In representative embodiments, the pacing ismyocardial pacing. In representative embodiments, the pacing isepicardial pacing.

A feature of the manner in which data from the flow meter is employed tomodulate pacing is that the modulation is automatic, by which is meantthat the modulation occurs without a human operator first evaluating theflow data and then directly or manually modulating the pacing element.Instead, a processing means in operational communication with the flowmeter and the pacing element automatically modulates the activity of thepacing element based on input received from the flow meter, e.g., byselecting an appropriate pacing protocol or routine based onpredetermined flow parameters. Accordingly, in representativeembodiments, the processing means may match or pair the observed flowdata with a set of different predetermined flow parameters, and thenselect a pacing routine which is paired with the best matched flowparameter of the set.

As indicated above, practice of the subject methods results in amodulation of function of the target valve. By modulation of function ismeant a change or alteration in the manner which the target valvemechanically operates, e.g., in controlling fluid flow across betweenregions separated by the valve. In many embodiments, the modulation isan improvement in the mechanical functioning of the valve, such that thevalve functions in a manner that more approximates the functioning of a“normal” valve, which is an analogous valve from a subject in normalhealth.

Systems

Also provided are systems for use in practicing the subject methods,where the systems include at least: a target valve structural alterationelement, a flow monitoring element, a pacing element and a processingelement that provides for the operational communication between the flowmeter and pacing elements, as described above. In certain embodiments,one or more of the various elements are integrated into a singlestructure, e.g., such as an integrated annuplasty and electromagneticflow measurement device as described above. Representative embodimentsof each of the above elements of the subject systems have been providedabove.

In addition, the subject systems may further include one or moreadditional components which are useful and/or needed for successfuloperation of the system. For example, the system may further include apower supply element, e.g., a battery. The system may further include areceiving element for receiving data and/or power remotely, such as atelemetric receiving element for receiving power and/or instructionsfrom a remote location, e.g., outside of the body, radiofrequencyreceiving element, optical receiving element, etc.

Computer-Related Embodiments

The invention also provides a variety of computer-related embodiments.Specifically, the invention provides programming for a processing meansthat can control a system as described above. The programming may becoded onto computer-readable medium, and the programming and theprocessor may be part of a computer based system.

In representative embodiments, the above methods are coded onto acomputer-readable medium in the form of “programming”, where the term“computer readable medium” as used herein refers to any storage ortransmission medium that participates in providing instructions and/ordata to a computer for execution and/or processing. Examples of storagemedia include floppy disks, magnetic tape, CD-ROM, a hard disk drive, aROM or integrated circuit, a magneto-optical disk, or a computerreadable card such as a PCMCIA card and the like, whether or not suchdevices are internal or external to the computer. A file containinginformation may be “stored” on computer readable medium, where “storing”means recording information such that it is accessible and retrievableat a later date by a computer.

With respect to computer readable media, “permanent memory” refers tomemory that is permanent. Permanent memory is not erased by terminationof the electrical supply to a computer or processor. Computer hard-driveROM (i.e. ROM not used as virtual memory), CD-ROM, floppy disk and DVDare all examples of permanent memory. Random Access Memory (RAM) is anexample of non-permanent memory. A file in permanent memory may beeditable and re-writable.

A “computer-based system” refers to the hardware means, software means,and data storage means used to analyze the information of the presentinvention.

The minimum hardware of the computer-based systems of the presentinvention comprises a central processing unit (CPU), input means, outputmeans, and data storage means. A skilled artisan can readily appreciatethat any one of the currently available computer-based system aresuitable for use in the present invention. The data storage means maycomprise any manufacture comprising a recording of the presentinformation as described above, or a memory access means that can accesssuch a manufacture.

To “record” data, programming or other information on a computerreadable medium refers to a process for storing information, using anysuch methods as known in the art. Any convenient data storage structuremay be chosen, based on the means used to access the stored information.A variety of data processor programs and formats can be used forstorage, e.g. word processing text file, database format, etc.

A “processor” references any hardware and/or software combination whichwill perform the functions required of it. For example, any processorherein may be a programmable digital microprocessor such as available inthe form of a electronic controller, mainframe, server or personalcomputer (desktop or portable). Where the processor is programmable,suitable programming can be communicated from a remote location to theprocessor, or previously saved in a computer program product (such as aportable or fixed computer readable storage medium, whether magnetic,optical or solid state device based). For example, a magnetic medium oroptical disk may carry the programming, and can be read by a suitablereader communicating with each processor at its corresponding station.

Utility

The subject invention finds use in valve function modulationapplications, and particular in methods of improving valve function,e.g., in the treatment of a given disease or condition. By treatment ismeant at least an amelioration of the symptoms associated with thedisease condition afflicting the host, where amelioration is used in abroad sense to refer to at least a reduction in the magnitude of aparameter, e.g. symptom, associated with the pathological conditionbeing treated, such as size of tumor, rate of growth of tumor, spread oftumor, etc. As such, treatment also includes situations where thepathological condition, or at least symptoms associated therewith, arecompletely inhibited, e.g., prevented from happening, or stopped, e.g.terminated, such that the host no longer suffers from the pathologicalcondition, or at least the symptoms that characterize the pathologicalcondition.

In certain representative embodiments where the target valve is a mitralvalve and the condition or disease being treated is mitral valveregurgitation or leakage, practice of the subject methods can beevaluated or measured by a reduction in the levels of symptomsassociated with heart failure, as classified by the New York HeartAssociation (NYHA) functional classification system. In thisclassification system, the levels range from a Class 1 level that isassociated with an asymptomatic patient who has substantially nophysical limitations to a Class 4 level which is associated with apatient who is unable to carry out any physical activity withoutdiscomfort, and has symptoms of cardiac insufficiency even at rest. Ingeneral, correcting for mitral valve leakage or regurgitation viapractice of the subject invention may be successful in allowing the NYHAclassification grade of a patient to be reduced. For instance, a patientwith a Class 4 classification may have his classification reduced toClass 3 and, hence, be relatively comfortable at rest. In yet otherembodiments, a patient with a Class 3 classification may have hisclassification reduced to Class 2, or a Class 2 patient may have hisclassification reduced to a Class 1, thereby resulting in improvement ofthe patient condition.

Kits

Also provided are kits for use in practicing the subject methods, wherethe kits typically include one or more of the above devices, and/orcomponents of the subject systems, as described above. As such, arepresentative kit may include a device, such as implantableannuloplasty device, as described above. The kit may further includeother components which may find use in practicing the subject methods.

In addition to above—mentioned components, the subject kits typicallyfurther include instructions for using the components of the kit topractice the subject methods. The instructions for practicing thesubject methods are generally recorded on a suitable recording medium.For example, the instructions may be printed on a substrate, such aspaper or plastic, etc. As such, the instructions may be present in thekits as a package insert, in the labeling of the container of the kit orcomponents thereof (i.e., associated with the packaging or subpackaging)etc. In other embodiments, the instructions are present as an electronicstorage data file present on a suitable computer readable storagemedium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actualinstructions are not present in the kit, but means for obtaining theinstructions from a remote source, e.g. via the Internet, are provided.An example of this embodiment is a kit that includes a web address wherethe instructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

The following examples are offered by way of illustration, and not byway of limitation.

EXPERIMENTAL I. Example of System with Interstitial Annuloplasty Device

FIG. 6 provides a view of a mitral valve treated according to thesubject invention with an interstitial annuloplasty device. In thesystem represented in FIG. 7, a peri-valvular implant is inserted aroundthe insufficient valve to bring the valvular orifice to a desired sizeand shape, thereby restoring the valvular function to an optimal level.The valvular implant is equipped with technology to sense transvalvularflow and detect valvular leakage. Additionally, epicardial electrodesare placed in association with weakened and/or arrhythmic segments ofthe heart. Both, the valvular implant and the epicardial electrodes areconnected to a central processing unit which coordinates the degree oftransvalvular flow with subsequent pacing of individualized segments ofthe myocardium. Specifically, FIG. 7 shows the anterior view of theheart. In FIG. 7, a malfunctioning mitral valve (1) is surgicallytreated with an interstitial implant (2), which restores the size andshape of the valve. Addition, the interstitial perivalvular implant (2)is equipped with sensing technology to monitory transvalvular flow, anddetect leakage of the valve. Information from the perivalvular sensorsis transmitted through connection wires (6) which could perforateanatomical heart barriers such as the atrial septum (4) in order toreach desired anatomical paths such as the superior cava vein, en routeto a remotely implanted pace maker (central processing unit), (notdepicted). The transvalvular flow monitor (2) receives energy andtransmits information through connection wires (6). Additionally, pacingelectrodes (3) for stimulation of myocardial segments are inserted intoclose proximity to the surface of the heart, e.g. in the coronary venoussystem (8). The pacing electrodes (3) receive energy and coordinationfrom a remotely implanted pace maker (central processing unit) throughwire connections (5). FIG. 8 depicts the operational relationship of thesystem components.

As evidenced by the above, the present invention provides methods andsystems for improving valve malfunction, which methods and systems arecharacterized by coupling mechanical repair of heart valve withelectrical stimulation of the associated heart segments to restore pumpfunction. In representative embodiments, an interstitial implant isinserted around an insufficient mitral valve to bring the valvularorifice to a desired size and shape, thereby restoring the valvularfunction to an optimal level. The interstitial valvular implant isequipped with technology to sense transvalvular flow and detect valvularleakage. Additionally, epicardial electrodes are placed in associationwith weakened and/or arrhythmic segments of the heart. Both theinterstitial valvular implant and the epicardial electrodes areconnected to a central processing unit which coordinates the degree oftransvalvular flow with subsequent pacing of individualized segments ofthe myocardium, thereby providing for improvement in valve and heartfunction. Accordingly, the present invention represents a significantcontribution to the art.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A method of modulating the function of a cardiac valve in a heart and using a cardiac pacing protocol or routine for cardiac pacing, said method comprising: (a) structurally altering said cardiac valve for modulating a function thereof; (b) monitoring blood flow velocity by an implanted blood flow velocity measuring device through said structurally altered cardiac valve; (c) pacing said heart by an implanted cardiac pacing device in response to said monitoring to modulate function of said cardiac valve; and (d) receiving blood flow velocity information from said implanted blood flow velocity measuring device by an implanted processing element in operational communication with said blood flow velocity measuring device and said cardiac pacing device, said implanted processing element transmitting data relating to a cardiac pacing protocol or routine to said implanted cardiac pacing device by selecting the cardiac pacing protocol or routine based on predetermined blood flow velocity information, wherein said implanted processing element is operative without operator evaluation of the blood flow velocity information to automatically modulate the activity of said implantable cardiac pacing device using the selected cardiac pacing protocol or routine.
 2. The method according to claim 1, wherein said modulating results in an improvement in said cardiac valve function.
 3. The method according to claim 2, wherein said cardiac valve is a mitral valve.
 4. The method according to claim 3, wherein said structurally altering comprises performing an annuloplasty procedure on said mitral valve.
 5. The method according to claim 4, wherein said annuloplasty procedure employs an implantable annuloplasty device.
 6. The method according to claim 5, wherein said annuloplasty device is an interstitial device.
 7. The method according to claim 1, wherein said blood flow velocity measuring device is a sonic device.
 8. The method according to claim 1, wherein said blood flow velocity measuring device is an optical device.
 9. The method according to claim 1, wherein said blood flow velocity measuring device is a thermal device.
 10. The method according to claim 1, wherein said blood flow velocity measuring device is an electromagnetic device.
 11. The method according to claim 1, wherein said blood flow velocity measuring device is in operational communication with an implanted cardiac pacing device.
 12. The method according to claim 1, wherein said blood flow velocity measuring device is integrated with an implantable annuloplasty device employed in said structural altering step.
 13. The method according to claim 12, wherein said blood flow velocity measuring device is an electromagnetic device.
 14. The method according to claim 1, wherein said pacing is epicardial pacing.
 15. The method according to claim 1, wherein said method is a method of improving function of a mitral valve, wherein said method comprises structurally altering said mitral valve by employing an interstitial annuloplasty device; wherein said monitoring comprises employing an electromagnetic blood flow velocity measurement element integrated with said interstitial annuloplasty device, wherein said blood flow velocity measuring device is in operational communication with an implanted cardiac pacing device that paces said heart according to step (c).
 16. A system for modulating the function of a cardiac valve in a heart and using a cardiac pacing protocol or routine for cardiac pacing, said system comprising: (a) an implantable device for structurally altering a cardiac valve for modulating a function thereof; (b) an implantable blood flow velocity measuring device for monitoring blood flow velocity through a cardiac valve; (c) an implantable cardiac pacing device in operational communication with said blood flow velocity measuring device; (d) a storage medium for storing a plurality of cardiac pacing protocols or routines, and (e) an implantable processing element in operational communication with said blood flow velocity measuring device and said cardiac pacing device, said implantable processing element receiving blood flow velocity information from said blood flow velocity measuring device and transmitting information relating to a cardiac pacing protocol or routine to said cardiac pacing device; wherein said implantable processing element is operative without operator evaluation of the blood flow velocity information to automatically modulate the activity of said cardiac pacing device based on the cardiac pacing protocol or routing; wherein the implantable processing element selects at least one of the cardiac pacing protocols or routines from the storage medium based on predetermined blood flow velocity information.
 17. The system according to claim 16, wherein said cardiac valve is a mitral valve.
 18. The system according to claim 16, wherein said implantable device is an annuloplasty device.
 19. The system according to claim 1, wherein said annuloplasty device is a surgically implanted device.
 20. The system according to claim 19, wherein said annuloplasty device is an interstitial device.
 21. The system according to claim 16, wherein said blood flow velocity measuring device is a sonic device.
 22. The system according to claim 16, wherein said blood flow velocity measuring device is an optical device.
 23. The system according to claim 16, wherein said blood flow velocity measuring device is a thermal device.
 24. The system according to claim 16, wherein said blood flow velocity measuring device is an electromagnetic device.
 25. The system according to claim 16, wherein said blood flow velocity measuring device is integrated with said implantable device for structurally altering a cardiac valve.
 26. The system according to claim 25, wherein said implantable device is an annuloplasty device.
 27. The system according to claim 26, wherein said annuloplasty device is a surgically implanted device.
 28. The system according to claim 27, wherein said annuloplasty device is an interstitial device.
 29. The system according to claim 28, wherein said blood flow velocity measuring device is an electromagnetic device.
 30. An implantable system for structurally altering a cardiac valve and providing cardiac pacing protocol or routine information, wherein said implantable system comprises: an implantable device for structurally altering a cardiac valve for modulating a function thereof; an integrated blood flow velocity measuring device, said device operational for providing cardiac pacing data in the form of a cardiac pacing protocol or routine to an implantable cardiac pacing device for pacing a heart by electrical stimulation in response to measured blood flow velocity information by said blood flow velocity measuring device; a storage medium for storing a plurality of cardiac pacing protocol or routines; and an implantable processing element in operational communication with said blood flow velocity measuring device, said storage medium and said cardiac pacing device, said implantable processing element receiving information from said blood flow velocity measuring device and transmitting to said cardiac pacing device a cardiac pacing protocol or routine based on predetermined blood flow velocity information; wherein said implantable processing element is operative without operator evaluation of the blood flow velocity information to automatically modulate the activity of said cardiac pacing device by selecting the cardiac pacing protocol or routine based on predetermined blood flow velocity information.
 31. The system according to claim 30, wherein said cardiac valve is a mitral valve.
 32. The system according to claim 31, wherein said implantable device is an annuloplasty device.
 33. The system according to claim 32, wherein said annuloplasty device is a surgically implanted device.
 34. The system according to claim 33, wherein said annuloplasty device is an interstitial device.
 35. The system according to claim 30, wherein said blood flow velocity measuring device is a sonic device.
 36. The system according to claim 30, wherein said blood flow velocity measuring device is an optical device.
 37. The system according to claim 30, wherein said blood flow velocity measuring device is a thermal device.
 38. The system according to claim 30, wherein said blood flow velocity measuring device is an electromagnetic device.
 39. The system according to claim 30, further including a cardiac pacing device in operational communication with said blood flow velocity measurement device.
 40. A kit for modulating the function of a cardiac valve in a heart and using a cardiac pacing protocol or routine, said kit comprising: (a) an implantable device for structurally altering a cardiac valve for modulating a function thereof; (b) an implantable blood flow velocity measuring device for monitoring blood flow through a cardiac valve; (c) an implantable cardiac pacing device for providing electrical stimulation to a heart in operative communication with said blood flow velocity measuring device, wherein said electrical pacing stimulation is in the form of a cardiac pacing protocol or routine; (d) a storage medium for storing a plurality of cardiac pacing protocols or routines; and (e) an implantable processing element in operational communication with said blood flow velocity measuring device, said storage medium and said cardiac pacing device, said implantable processing element receiving information from said blood flow velocity measuring device and transmitting to said cardiac pacing device a cardiac pacing protocol or routine based on predetermined blood flow velocity information; wherein said implantable processing element is operative without operator evaluation of the blood flow velocity information to automatically modulate the activity of said cardiac pacing device.
 41. The kit according to claim 40, wherein said cardiac valve is a mitral valve.
 42. The kit according to claim 41, wherein said implantable device is an annuloplasty device.
 43. The kit according to claim 42, wherein said annuloplasty device is a surgically implanted device.
 44. The kit according to claim 43, wherein said annuloplasty device is an interstitial device.
 45. The kit according to claim 40, wherein said blood flow velocity measuring device is a sonic device.
 46. The kit according to claim 40, wherein said blood flow velocity measuring device is an optical device.
 47. The kit according to claim 40, wherein said blood flow velocity measuring device is a thermal device.
 48. The kit according to claim 40, wherein said blood flow velocity measuring device is an electromagnetic device.
 49. The kit according to claim 40, wherein said blood flow velocity measuring device is integrated with said implantable device for structurally altering a cardiac valve.
 50. The kit according to claim 49, wherein said implantable device is an annuloplasty device.
 51. The kit according to claim 50, wherein said annuloplasty device is a surgically implanted device.
 52. The kit according to claim 51, wherein said annuloplasty device is an interstitial device.
 53. The kit according to claim 50, wherein said blood flow velocity measuring device is an electromagnetic device.
 54. The kit according to claim 40, wherein said cardiac pacing device is an epicardial pacing device.
 55. The kit according to claim 40, wherein said kit further comprises instructions for using said kit. 